Nephroprotective Effects of the Dual GCGR / GLP ‐ 1R Agonist Survodutide in Hypertension‐Accelerated Diabetic Kidney Disease

Aims Survodutide is a novel long‐acting dual glucagon (GCGR)/glucagon‐like peptide‐1 (GLP‐1R) receptor agonist currently in phase‐3 clinical development for the treatment of people living with obesity and metabolic dysfunction‐associated steatohepatitis. Emerging evidence suggests impaired renal GCGR function in chronic kidney disease (CKD), including diabetic kidney disease (DKD). This study aimed to characterize the effects of survodutide in a translational mouse model of advanced DKD, induced by adeno‐associated virus‐mediated renin overexpression (ReninAAV) in uninephrectomized (UNx) diabetic db/db mice. Materials and Methods Female obese and diabetic db/db C57BKS mice received a single intravenous dose of ReninAAV 1 week prior to UNx. Three weeks post‐UNx, db/db UNx‐ReninAAV mice were administered (s.c., q.d.) vehicle or survodutide (7.5 nmol/kg) for 10 weeks. Endpoints included blood/urine biochemistry, histological markers of glomerulosclerosis, tubular injury and inflammation, as well as quantitative 3D whole‐pancreas and whole‐kidney imaging. Results Compared to vehicle controls, survodutide reduced body weight, hyperglycemia, and HbA1c levels concurrent with improved hyperinsulinemia and β‐cell islet volume distribution. Notably, survodutide promoted substantial benefits on advanced albuminuria, severe glomerulosclerosis, kidney hypertrophy and inflammation. 3D whole‐kidney imaging revealed that survodutide significantly reduced kidney and glomerular hypertrophy while increasing glomerular density and improving glomerular sphericity. Survodutide reduced liver weight and plasma amino acid levels, including alanine, confirming hepatic glucagon receptor activation. Conclusions Survodutide markedly improved metabolic and renal outcomes in the db/db UNx‐ReninAAV mouse model of advanced DKD, supporting further investigation into therapeutic options of survodutide in chronic kidney diseases.